Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists

Satoshi Yamamoto, Nobuyuki Matsunaga, Takenori Hitaka, Masami Yamada, Takahito Hara, Junichi Miyazaki, Takashi Santou, Masami Kusaka, Masuo Yamaoka, Naoyuki Kanzaki, Shuichi Furuya, Akihiro Tasaka, Kazumasa Hamamura, Mitsuhiro Ito

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5- (hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3- carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.

Original languageEnglish
Pages (from-to)422-434
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number1
DOIs
Publication statusPublished - Jan 1 2012
Externally publishedYes

Keywords

  • 1-Arylmethyl-4-phenylpyrrole derivatives
  • Androgen receptor antagonists
  • Castration-resistant prostate cancers

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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